Gadolinium-based contrast agents (GBCAs) enhance visualization by MRI of abnormalities in the central nervous system (CNS) and associated cerebral vasculature. Recent studies have heightened concern about the safety of unstable GBCAs, and potential adverse effects of gadolinium (Gd) deposition in the brain, bone and other organs. Clinicians should be aware of the ongoing controversy and considerations for patients’ health prior to and after Gd-enhanced MRI procedures.
A primary concern with GBCAs has been the very rare incidence of nephrogenic systemic fibrosis (NSF) that purportedly only occurs in patients with severe kidney dysfunction. Extremely painful NSF is a scleromyxedema-like cutaneous disease with joint contractures that may progress to multisystem organ failure (< 1% incidence, about 31% mortality). Other proposed risk factors for GBCA-induced NSF now include acute and moderate chronic renal failure, major proinflammatory states, and high-dose erythropoietin use. Recently “gadolinium deposition disease” (GDD) has been coined to describe additional symptoms that may be associated with exposure to GBCAs. Even patients with normal renal function may exhibit progressive symptomatology beyond the time frame of severe acute adverse events. Although apparently rare, symptoms of GDD are less severe than NSF, and may include central and peripheral pain, headache, bone pain, skin thickening, muscle weakness, arthralgia, and persistent clouded mentation.
Heightened concern regarding GDD and GBCAs has been instigated by the results of a plethora of recent studies that found significant Gd deposits in the brains of cadavers and patients after multiple Gd-enhanced MRIs. Dose related Gd deposition in the globus pallidus, dentate nucleus, and thalamus have been emphasized. Brain Gd levels correlated with cumulative doses of GBCAs. The potential clinical implications of Gd deposition in the brain is unknown. After issuing a strong cautionary statement about limiting exposure to GBCAs, the F.D.A. decided not to restrict the use of any of the GBCAs– including certain GBCAs that are associated with a higher retention of Gd.
The linear verses macrocyclic chelate structures of GBCAs affect the rate of release of free Gd in the body. The commonly used DTPA-based linear “wrap around” agents (Omniscan®, Magnavist®) have reported Gd disassociation half-lives of 0.5 and 10 minutes, respectively. The more stable ionic macrocyclic (“cage-like”) agent Dotarem® has a disassociation half-life of > 30 days. Greater retention of Gd has been associated with the less stable linear GBCAs; accordingly very specific labeling warnings have been mandated in some countries.
A new chelator HOPO has been approved for a first-in-human Phase 1 safety trial. Due to its unique coordination chemistry HOPO binds Gd in a manner that renders it useless as a GBCA. The compound is orally bioavailable, distributes to the brain and bone and is excreted primarily in bile. Such a compound might be used immediately after Gd-enhanced MRI.
Suggestions for clinicians It seems prudent to first ascertain the absolute necessity for the use of a GBCA, especially if there has been previous exposure. If deemed essential (e.g. brain imaging), one might insist upon administration of the most appropriate stable macrocyclic GBCA. Objectively access current kidney function (GFR). Be mindful of new symptoms after the procedure- if consistent with GDD assess the urinary level of Gd (24-hour of 1st morning void collection). Although not formally studied, chelation therapy (Ca-EDTA) might be considered.